Optimization of Brigatinib as New Wild-Type Sparing Inhibitors of EGFR Mutants.

A series of brigatinib derivatives were designed and synthesized as new potent and selective EGFR inhibitors. One of the most potent and selective compounds strongly suppressed the EGFR and EGFR kinases with IC values of 0.7 and 3.6 nM, respectively, which were over 54-fold more potent than the lead compound. also demonstrated promising EGFR mutant selectivity, and was 94-fold less potent against the wild type EGFR. A cocrystal structure of EGFR with a close derivative was solved to provide insight on the inhibitor's binding mode. Moreover, compound was orally bioavailable and demonstrated highly desirable PK properties, making it a promising lead compound for further structural optimization.